Project Summary Osteoporosis, a disease of bone fragility predisposing an individual to fracture, is a major public health problem. Over two million osteoporotic fractures occur per year, resulting in greater than $17 billion in direct annual costs for fracture care. Hip fractures account for 70% of these costs as they have the most devastating clinical consequences; the mortality rate in the first year after hip fracture is as high as 24%. Osteoporosis is caused by reduced bone mass and deterioration in bone microarchitecture, which together weaken bone. Several bone-strengthening drugs are available to reduce fracture risk, and in placebo-controlled trials, these drugs have different efficacies for fracture risk reduction depending on the skeletal site. Unfortunately, it is unknown which drug or drug combination works best to reduce overall fracture risk and in particular fracture risk in the hip. This gap in knowledge exists because clinical trialists lack an endpoint in the hip that would permit superiority trials -- aimed at determining the best bone-strengthening drug or regimen -- to be performed with feasible costs, sample sizes, and follow-up times. Currently, fracture and bone mineral density (BMD) are the Food and Drug Administration (FDA)-approved endpoints used in clinical trials, but fractures have a low incidence and BMD changes very slowly. In addition, changes in BMD after therapy only reflect 4-52% of the variance in fracture risk reduction. As a result, tens of thousands of subjects are necessary to power head-to- head, active comparator trials aimed at demonstrating the superiority of one agent over another. Bone microarchitecture has not routinely been monitored in osteoporosis clinical trials, even though its deterioration is included in the World Health Organization disease definition of osteoporosis. We have recently demonstrated the feasibility of imaging hip microarchitecture in vivo using a clinical magnetic resonance imaging (MRI) scanner. We have shown that assessment of hip microarchitectural parameters (via digital and volumetric topological analysis) and strength (via finite element analysis) is reproducible and provides information about bone quality and fracture risk that is not captured by DXA. Unlike computed tomography (CT), MRI can image at a resolution high enough to depict bone microarchitecture and does not administer ionizing radiation, which is ideal for short-term serial imaging. And unlike prior microarchitectural imaging studies, which have been performed in the distal radius or distal tibia using either MRI or high-resolution peripheral quantitative computed tomography (HR-pQCT), we can now image bone microarchitecture in the hip, the most devastating fracture site. In this study, we now aim to demonstrate the value of the MRI test, beyond the value of DXA, for monitoring short-term therapy response in the hip. This work will lay the foundation for the use of hip microarchitecture and strength, in addition to hip BMD, as a biomarker of treatment response in multicenter studies and as a potential surrogate endpoint to reduce sample sizes and accelerate osteoporosis clinical trials. This will reduce the burden of osteoporotic fractures on society.